Fas-mediated apoptosis is an essential mechanism for maintenance of immune homeostasis. The expression of Fas is regulated at transcriptional and protein levels. Furthermore, several death domain molecules and caspases are crucial downstream mediators and executioners of Fas-mediated apoptosis. A tightly regulated interaction of these molecules ensures normal immune functions, including the execution of activation-induced cell death, T-cell mediated cytotoxicity, and surveillance of immune privileged tissues. In contrast, abnormally increased or decreased Fas-mediated apoptosis is a major pathogenic mechanism of several diseases, including systemic or tissue-specific autoimmune diseases and immune deficiency. Two CD2-fas transgenic mouse lines are described here to demonstrate the importance of controlling Fas-mediated apoptosis. Correction of Fas in Fas-mutant mice restored apoptosis function and ameliorated autoimmune symptoms, whereas a long-term enhancement of Fas expression in Fas-normal mice resulted in an increased acute-phase response and renal amyloidosis in aged transgenic mice.